Comprehensive evaluation of time-varied outcomes for invasive and conservative strategies in patients with NSTE-ACS: a meta-analysis of randomized controlled trials

Background Results from randomized controlled trials (RCTs) and meta-analyses comparing invasive and conservative strategies in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) are highly debatable. We systematically evaluate the efficacy of invasive and conservative strategies in NSTE-ACS based on time-varied outcomes. Methods The RCTs for the invasive versus conservative strategies were identified by searching PubMed, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials.gov. Trial data for studies with a minimum follow-up time of 30 days were included. We categorized the follow-up time into six varied periods, namely, ≤6 months, 1 year, 2 years, 3 years, 5 years, and ≥10 years. The time-varied outcomes were major adverse cardiovascular event (MACE), death, myocardial infarction (MI), rehospitalization, cardiovascular death, bleeding, in-hospital death, and in-hospital bleeding. Risk ratios (RRs) and 95% confidence intervals (Cis) were calculated. The random effects model was used. Results This meta-analysis included 30 articles of 17 RCTs involving 12,331 participants. We found that the invasive strategy did not provide appreciable benefits for NSTE-ACS in terms of MACE, death, and cardiovascular death at all time points compared with the conservative strategy. Although the risk of MI was reduced within 6 months (RR 0.80, 95% CI 0.68–0.94) for the invasive strategy, no significant differences were observed in other periods. The invasive strategy reduced the rehospitalization rate within 6 months (RR 0.69, 95% CI 0.52–0.90), 1 year (RR 0.73, 95% CI 0.63–0.86), and 2 years (RR 0.77, 95% CI 0.60–1.00). Of note, an increased risk of bleeding (RR 1.80, 95% CI 1.28–2.54) and in-hospital bleeding (RR 2.17, 95% CI 1.52–3.10) was observed for the invasive strategy within 6 months. In subgroups stratified by high-risk features, the invasive strategy decreased MACE for patients aged ≥65 years within 6 months (RR 0.68, 95% CI 0.58–0.78) and 1 year (RR 0.75, 95% CI 0.62–0.91) and showed benefits for men within 6 months (RR 0.71, 95% CI 0.55–0.92). In other subgroups stratified according to diabetes, ST-segment deviation, and troponin levels, no significant differences were observed between the two strategies. Conclusions An invasive strategy is superior to a conservative strategy in reducing early events for MI and rehospitalizations, but the invasive strategy did not improve the prognosis in long-term outcomes for patients with NSTE-ACS. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289579, identifier PROSPERO 2021 CRD42021289579.

Page 7 Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.
Page 7 Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.
Page 7; Table S3 10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.
Page 7 Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process. against the planned groups for each synthesis (item #5)). Table S2 13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions. Page7 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. Page 7 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.
Page 8 13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression). Page 8 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results. Page 8 Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases). Page 8 Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. Page 8

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
Page 9; Figure 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. Page 9 Study characteristics 17 Cite each included study and present its characteristics. Page 9;  19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.
Page 10-13 20c Present results of all investigations of possible causes of heterogeneity among study results. Page 13-14; Table S4 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results. Page 13;

OTHER INFORMATION
Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered. Page 6 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared. Page 6 24c Describe and explain any amendments to information provided at registration or in the protocol. None Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review. Page 1 Competing interests 26 Declare any competing interests of review authors. Page 18 Availability of data, code and other 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.  (1) Age ≥80 years;

Item
(2) NSTE-ACS with ischemic symptoms lasting over 10 min in the previous 72 h; and (3) ST-segment depression 1 mm and/or elevated, troponin T or CK-MB.
Invasive strategy included native coronary and bypass graft angiography and coronary and graft revascularization with PCI and CABG, as clinically appropriate.
Conservative strategy was medical therapy, and could be referred for invasive management if prespecified criteria occurred post-randomization.
Invasive strategy group received routine cardiac catheterization within 72 h of admission.
Conservative patients underwent only medical treatment, and cardiac catheterization was allowed in the case of recurrent ischemia or heart failure after admission, or in the case of a positive predischarge non-invasive stress test. (1) Typical chest pain for UA with the last pain episode occurring within 24 hours prior to admission;

NSTE-ACS
(2) ECG ST-segment abnormalities; and (3) cardiac troponin I value above the upper limit of the norm.
Unwillingness or inability to sign informed consent for coronary arteriography or PCI.
Invasive strategy was scheduled to undergo CAG and PCI within 24 hours after admission.
Patients assigned to the conservative strategy were medically stabilized at first, with CAG required only in case of angina recurrence and/or evidence of inducible myocardial ischemia.
Invasive strategy included CAG within 72 h and, when indicated, coronary revascularization by either PCI or CABG according to coronary anatomy, patient preference, and local skills.
Conservative therapy was medical therapy, and CAG during index hospital was allowed in the case of refractory ischemia, myocardial (re)infarction, heart failure of ischemic origin, or malignant ventricular arrhythmias.
Patients assigned to the invasive strategy were scheduled to undergo CAG by a time window of 10-48 h after randomization.
Patients assigned to the conservative strategy were initially treated medically, with immediate intervention required only if the patients met prespecified criteria.
Invasive strategy was a routine CAG within 4 days of admission and, if appropriate, revascularization within 7 days of admission.
Patients randomized to the conservative strategy underwent CAG only if they experienced symptoms or signs of severe ischaemia.

NSTE-ACS
Netherlands 45 [2001][2002][2003] (1) NSTE-ACS with ischemia symptoms increasing or occurred at rest within 24 hours; (1) Age <80 years; (2) ST elevation or depression or T wave inversion, or creatine kinase elevation 2 times the upper limit of normal and/or elevation in CK-MB, troponin T, or troponin I; and (3) treated with aspirin plus heparin and/or a glycoprotein IIb/IIIa inhibitors for a minimum of 48 hours.
(1) New pathological Q wave on ECG; (2) one or more of the following: shock, congestive heart failure, ventricular arrhythmia, recurrent or persistent chest pain or myocardial ischemia; (3) contraindications to repeat cardiac procedures; (4) primary PCI during the current admission or angiography, PCI, or CABG within 6 months; (5) contraindications or inability to undergo treadmill testing; (6) life expectancy <1 year; or (7) being unlikely to be available for follow-up stress testing.
Patients randomized to the invasive arm underwent angiography at 2 to 5 days following their NQWMI Patients randomized to the noninvasive arm underwent stress testing (stress echocardiography or stress nuclear perfusion imaging) at 2 to 5 days following their NQWMI.
Obviously at high risk of death or myocardial infarction. Patients undertook CAG within 72 h in the interventional strategy with subsequent management guided by the angiographic findings.
Patients assigned to the conservative strategy were managed with antianginal and antithrombotic medication VINO NSTEMI Czech Republic 2 1998-2000 (1) Rest ischaemic chest pain, lasting more than 20 min within 24 h; (2) ECG evidence of acute myocardial ischaemia without ST-segment elevations; and (3) CK-MB higher than 1·5× upper limit of normal and/or positive troponin I assay.
Invasive strategy characterized by CAG as soon as possible followed by immediate coronary angioplasty of the culprit coronary lesion+stent implantation whenever suitable.

Multi
(2) secondary angina; (3) a history of PCI or CABG within 6 months; (4) factors associated with an increased risk of bleeding; (5) left bundle-branch block or paced rhythm; (6) severe congestive heart failure or cardiogenic shock; (7) serious systemic disease; (8) serum creatinine level of more than 2.5 mg per deciliter; (9) participation in another study; (10) taking warfarin or ticlopidine or clopidogrel for more than three days.
Invasive strategy was to undergo CAG between 4 and 48 hours after randomization and revascularization when appropriate on the basis of coronary anatomical findings.
Patients assigned to conservative strategy were treated medically, and were to undergo CAG and revascularization as appropriate only if they had symptoms like recurrent angina and so on.
TRUCS UA Greece 576 [1997][1998] (1) Primary unstable angina and post-infarction angina; and (2) did not suffer a new myocardial infarction or death within the first 48 h post admission and subsequently developed refractory unstable angina.
Patients refusing to give informed consent. Patients assigned to the invasive strategy underwent CAG locally, the day the diagnosis of refractory unstable angina was made.
Patients assigned to the conservative strategy were treated medically on the initial 'optimal' therapy regime with gradually increasing doses of nitrates and calcium antagonists unless contraindicated.
The invasive strategy included CAG and, if appropriate, revascularization within seven days of hospital admission.
The conservative strategy recommended CAG in patients with refractory or recurrent symptoms, despite maximal medical treatment or severe ischemia on a predischarge symptom-limited exercise test. woman of child-bearing potential; or (10) receiving oral anticoagulants. randomization.

MOSCA
Combination of all-cause mortality, reinfarction and readmission for cardiac cause (postdischarge revascularization or heart failure).
Death from any cause.
New episode of chest pain with troponin elevation after admission, during either the index hospital stay or a new readmission and readmission for cardiac cause.
Readmission for cardiac cause. Bleeding ≥ TIMI 2 according to the Thrombolysis in Myocardial Infarction bleeding criteria.

After Eighty
Combination of MI, need for urgent revascularization, stroke, and deaththe first occurring event.
Death from any cause. NA NA Major bleeding according to the Thrombolysis in Myocardial Infarction bleeding criteria.

Dimitrov et al
Combination of frequency of occurrence of recurrent angina, rehospitalization, coronary arteriography and intervention, development of MI, symptoms of heart failure, total mortality rate.
Death from any cause. NA NA NA

Italian Elderly ACS
Combination of all-cause mortality, nonfatal MI, disabling stroke, and repeat hospital stay for cardiovascular causes or severe bleeding.
Death from any cause. Nonfatal MI. Repeat hospital stay for cardiovascular causes or severe bleeding. Bleeding Academic Research Consortium grades 2, 3a, and 3b.
Moderate bleeding occurring either spontaneously, PCI-related, or CABG-related as assessed by the GUSTO definition and the occurrence of any ischaemic stroke.

OASIS 5
Combination of death, MI, or stroke. NA NA NA Major bleeding, defined as clinically overt bleeding with at least one of the following criteria: fatal, symptomatic intracranial haemorrhage, intraocular haemorrhage leading to significant vision loss or decrease in haemoglobin of 30 g/L, or requiring transfusion of 2 U of blood.

ICTUS
Combination of death, recurrent MI, or rehospitalization for angina within one year after randomization.
Death from any cause.
Documented myocardial necrosis, occurring either spontaneously or in the setting of percutaneous intervention.
Rehospitalization for anginal symptoms. NA

TACTICS-TIMI 18
Combination of death, nonfatal MI, and rehospitalization for an acute coronary syndrome.
Death from any cause. Nonfatal MI. Rehospitalization for an acute coronary syndrome NA

TRUCS
Combination of death and non-fatal MI. NA The occurrence of two of the three conventional criteria-typical chest pain, diagnostic electrocardiography recording (mainly new Q-wave), or a raised biochemical marker of myocardial damage.
Readmission for unstable angina. NA

FRISC-II
Combination of all-cause death and MI. Death from any cause.
The occurrence of two of the three conventional criteria-typical chest pain, diagnostic electrocardiography recording (mainly new Q-wave), or a raised biochemical marker of myocardial damage according to the following definitions.

NA
Major bleeding, defined as at least one of: leading to death; intracranial bleed; need for blood transfusion; decrease in haemoglobin of 40 g/L or more, irrespective of symptoms; and decrease in haemoglobin of more than 20 g/L associated with symptoms of bleeding.